Computational modelling of intracellular signalling pathways and the study of synaptic plasticity induction in the cerebellum

• Grant number: 13/17063-5
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): November 01, 2013
• Effective date (End): October 31, 2015
• Field of knowledge: Engineering - Biomedical Engineering - Bioengineering
• Principal Investigator: Antonio Carlos Roque da Silva Filho
• Grantee: Thiago Matos Pinto
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Many biochemical compounds are involved in the signalling networks that govern synaptic plasticity in the cerebellum. In particular, calcium-calmodulin dependent protein kinase II (CaMKII), which is highly concentrated in the brain, regulates forms of synaptic plasticity. Although significant progress has been made in understanding the role of postsynaptic CaMKII in plasticity in other brain areas, very little is known about its function during plasticity induction in the cerebellum. Cerebellar Purkinje cells (PCs) receive strong excitatory inputs from parallel fibres (PFs), and inhibitory inputs from molecular layer interneurons (MLIs), which have been historically divided into basket and stellate cells. The CaMKII holoenzyme is composed of different isoforms, such as alphaCaMKII and betaCaMKII, which is the predominant CaMKII isoform in the cerebellum. Our collaborators at the Erasmus Medical Center (Erasmus MC) Rotterdam have recently performed experiments with mutant mice, and demonstrated that betaCaMKII controls the direction of plasticity at the excitatory PF-PC synapse. More specifically, protocols that induce long-term depression (LTD) in wild-type mice result in long-term potentiation (LTP) in mutant mice that lack betaCaMKII, and vice versa. However, the underlying mechanism that may explain their experimental findings was not clear. The candidate for the "Bolsa de Pós-Doutorado" at the University of Hertfordshire (UK) has recently developed simple computational models of signalling pathways to study the CaMKII activation, and the role of betaCaMKII in the bidirectional plasticity at the PF-PC synapse. As a corollary, simulations have predicted interesting features of the CaMKII dependence on the frequency of calcium signals, and also indicated some mechanisms that may explain the involvement of betaCaMKII in the induction of LTD and LTP.In addition to the excitatory inputs from PFs, PCs also receive inhibitory inputs from MLIs. Several studies of synaptic plasticity at excitatory synapses have been reported, while for inhibitory synapses little information about the molecular mechanisms of plasticity induction is known. At the inhibitory MLI-PC synapse there is a postsynaptic form of plasticity called rebound potentiation (RP), which might play a role in motor learning in the cerebellum. Experimental and computational studies have suggested several molecular pathways at the MLI-PC synapse that may affect the induction of RP, but the entire signalling cascade is still unknown. Recent experimental findings from our collaborators at the Erasmus MC have indicated that the alphaCaMKII and betaCaMKII isoforms have important roles in the induction of RP at the MLI-PC synapse (unpublished). However, the mechanism that underlies their observations at this synapse remains elusive.The aim of this research project is to investigate the molecular mechanisms that mediate the induction of synaptic plasticity in the cerebellum. In particular, we are interested in the role of the alphaCaMKII and betaCaMKII isoforms in the plasticity induction at both PF-PC and MLI-PC synapses.To explore the signal transduction pathways in cerebellar LTD and LTP at the excitatory PF-PC synapse, we will extend computational models implemented by the candidate during his PhD research, and study the role of betaCaMKII in the bidirectional plasticity at this synapse. In addition to our research at the excitatory PF-PC synapse, we will also build a kinetic simulation model of the signalling pathways at the inhibitory MLI-PC synapse. We want to study the involvement of the alphaCaMKII and betaCaMKII isoforms in the induction of RP. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PINTO, THIAGO M.; SCHILSTRA, MARIA J.; ROQUE, ANTONIO C.; STEUBER, VOLKER. Binding of Filamentous Actin to CaMKII as Potential Regulation Mechanism of Bidirectional Synaptic Plasticity by beta CaMKII in Cerebellar Purkinje Cells. SCIENTIFIC REPORTS, v. 10, n. 1, JUN 2 2020. (13/17063-5, 13/07699-0, 15/50122-0)